Dibenzazepine derivatives and their preparation

ABSTRACT

The invention provides new 10-amino-10,11-dihydrodibenzo(b, f)azepine derivatives and their salts which are useful as antidepressants, analgesics, anticonvulsants and tranquillizers.

United States Patent [72] Inventors [21] Appl. No.

[22] Filed [45] Patented [73] Assignee [32] Priorities Jean ClementLouis Fouche Hauts-de-Seine; Claude Georges Alexandre Gueremy,Valde-Marne, both of France Jan. 17,1968

Nov. 23, 1971 Rhone-Poulenc S.A.

Paris, France Jan. 18, 1967 France Nov. 9, 1967, France, No. 127,611

[54] DIBENZAZEPINE DERIVATIVES AND THEIR PREPARATION 1 1 Claims, NoDrawings 8/1968 Switzerland Primary Examiner-Alton D. RollinsAttorney-Stevens, Davis, Miller & Mosher ABSTRACT: The inventionprovides new IO-amino-IOJ ldihydrodibenzolb,flazepine derivatives andtheir salts which are useful as anti-depressants, analgesics.anticonvuisants and tranquilizers.

DIBENZAZEPINE DERIVATIVES AND THEIR dihydrodibenzo[b,f]e-azepinederivatives of the formula:

and their acid addition salts and quaternary ammonium derivatives, inwhich R and R are the same or different'and represent hydrogen, alkyl ofone to five carbon atoms, hydroxyalkyl of one to five carbon atoms,hydroxyalkoxyalkyl of one to five carbon atoms in each alkyl residue,phenylalkyl of one to five carbon atoms in the alkyl residue,orphenylalkyl of one to five carbon atoms in the alkyl residue in whichthe phenyl nucleus is substituted by one or more of halogen, alkyl ofone to five carbon atoms, alkoxy of one to five carbon atoms, nitro,amino, or trifluoromethyl, and R, is hydrogen, alkyl of one to fivecarbon atoms, phenylalkyl of one to five carbon atoms in the alkylresidue, or phenylalkyl of one to five carbon atoms in the alkyl residuein which the phenyl nucleus is substituted by one or more of halogen,alkyl of one to five carbon atoms, alkoxy of one to five carbon atoms,or trifluoromethyl.

In accordance with the invention, the compounds of formula 1 areprepared by one of the following methods: I. The compounds of formula 1in which R and R are both hydrogen may be prepared by reducing acompound of the general formula:

in which R, is as hereinbefore defined, preferably by the action ofsodium in a saturated primary aliphatic alcohol of two to six carbonatoms, for example butanol, or by the action of sodium amalgam.

2. The compounds of formula I in which is of the formula N in which R ishydrogen, alkyl of one to four carbon atoms, hydroxyalkyl of one to fourcarbon atoms, hydroxyalkoxyalkyl of one to four carbon atoms in eachalkyl residue, phenyl, phenylalkyl of one to four carbon atoms in thealkyl residue, or phenylalkyl of one to four carbon atoms in the alkylresidue in which the phenyl nucleus is substituted by one or more ofhalogen, alkyl of one to five carbon atoms, alkoxy of one to five carbonatoms, amino, or trifluoromethyl, and R is hydrogen, alkyl of one tofive carbon atoms, phenylalkyl of one to five carbon atoms in the alkylresidue, or phenylalkyl of one to five carbon atoms in the alkyl residuein which the phenyl nucleus is substituted by one or more of halogen.alkyl of one to five carbon atoms, or trifluoromethyl, may be preparedby reducing a compound of the formula:

in which R,, R, and R are as hereinbefore defined, by any methodsuitable for reducing a carbonamide group to a methyleneamino group. Asreducing agent it is advantageous to employ lithium aluminum hydride'andto carry out the operation in when organic solvent such as an ether, forexample diethyl ether or tetr ahydrofuran.

3. The compounds of formula I in which represents the group -N Clin -R,

in which R, is aspreviously defined and R is hydrogen, alkyl of one tofivecarbon atoms, hydroxyalkyl of one to five carbon atoms,hydroxyalkoxyalkyl of one to five carbon atoms in each alkyl residue,phenylalkyl of one to five carbon atoms in the alkyl residue, orphenylalkyl of one to five carbon atoms in the alkyl residue in whichthe phenyl nucleus is substituted by one or more of halogen, alkyl ofone to five carbon atoms, alkoxy of one to five carbon atoms, amino,trifiuoromethyl, may be prepared by reacting a compound of the formula:

Rr-CHO IV 2 which R, is as previously defined, and hydrogen in thepresence of ahydrogenation catalyst, on a compound of the formula:

in which R, and R are as hereinbefore defined.

When this process is applied to compounds of formula V in which R, is ahydrogen atom, and two molecular proportions or more of the aldehyde offormula IV and hydrogen are employed, compounds of formula I areobtained, in which is ofthe formula -N(CH,-R

In all cases, it is advantageous to operate in a saturated lower primaryaliphatic alcohol such as ethanol and to employ ,Raney nickel or Adamsplatinum as hydrogenation catalyst.

In some cases, when it is desired to produce a compound in which'R, ishydrogen, it may be advantageous to react the al-,

dehyde of formula IV and the hydrogen with a compound of the formula:

R -NH V1:

in which Ac represents an acyl radical which may be readily eliminatedby acid hydrolysis and R is as previously defined. and then to eliminatethe Ac radical by hydrolysis.

N is of the formula N in which R is as hereinbefore defined, and R isalkyl of one to five carbon atoms, hydroxyalkyl of one to five carbonatoms, hydroxyalkoxyalkyl of one to five carbon atoms in each alkylresidue, phenylalkyl of one to five carbon atoms in the alkyl residue,or phenylalkyl of one to five carbon atoms in the alkyl residue in whichthe phenyl nucleus is substituted by one or more of halogen, alkyl ofone to five carbon atoms, alkoxy of one to five carbon atoms, nitro,amino, or trifiuoromethyl, may be prepared by reacting a compound of theformula:

R,-x VI in which R is as hereinbefore defined and X represents areactive ester residue such as a halogen atom or a sulphuric orsulphonic ester residue (for example a methanesulphonyloxy ortoluene-p-sulphonyloxy residue) with a compound of the formula:

is of the formula: -N( R,,),.

It is advantageous to operate in an inert organic solvent such asdimethylformamide-and in the presence of sodium bicarbonate, preferablyat the boiling temperature of the solvent.

5. The compounds of formula I in which is of the formula NHR in which R,is as hereinbefore defined, may be prepared by replacing,

in a compound of the formula:

iii N RsNY VII! in which R, and R, are as hereinbefore defined and Y iscyano. alkoxy, carbonyl, alkanoyl, alkanesulphonyl or arylsulphonylradical. the radical Y by a hydrogen atom. The replacement of theradical Y by hydrogen may be carried out by the usual methods specificto each of the meanings of Y.

6. The compounds of formula I in which is of the formlua N in which R,,is hydrogen or alkyl of one to live carbon atoms. may be prepared byreducing a compound of the formula:

by any method known per se for the preparation of oximes from ketones.

The compounds of formula X in which R, is other than hydrogen, may beprepared in accordance with German Pat. No. 1,142,870. This methodconsists in alkylating a compound of the formula:

CH: XI

with a compound of the formula:

R,X X" in which R, is the same as R,, but not hydrogen, and X is ashereinbefore defined, followed by hydrolyzing the intermediate for theformula:

thus obtained.

The compounds of fonnula III in which R, and R are as hereinbeforedefined may be prepared from compounds of the formula:

XIII

XIV

in which R, and R are as hereinbefore defined, by any method ofacylation known per se.

it appears particularly advantageous to employ a chloride or anhydrideof an acid of formula:

R COOH (where R is as hereinbefore defined) and to operate in an inertorganic solvent such as benzene or toluene, with reflux of the solventand in the presence or absence of a base such as a tertiary amine, forexample pyridine.

When R, in formula III is hydrogen, it is particularly advantageous tocarry out the acylation with ethyl formate and to operate in anautoclave at a temperature between 50 and 150 C.

The compounds of formula lX, in which R and R, are as hereinbeforedefined may be prepared by any method known per se for the preparationof urethanes from compounds of the formula:

in which R is as hereinbefore defined.

The compounds of formulae V, VI] and XIV, in which R, R and R, are ashereinbefore defined, but are not hydrogen, may be prepared bysuccessive application of one or more of the methods l to 6 describedherein to compounds of the formula:

NH: XVI

s- VIIIa in which R, and R are as hereinbefore defined. b. By alkylationof a compound of the formula:

in which R, and Y are as hereinbefore defined, with a reactive ester ofthe formula VI in the presence of an alkaline condensation agent.

The compounds of formula Vlllb may be obtained from compounds of theformula:

NE: V 1110 in which R, is as hereinbefore defined, by the action ofcyanogen bromide, an alkyl chloroformate, an acid halide or an aliphaticor aromatic sulphonyl chloride.

The compounds of formula I may optionally be purified by physicalmethods (such as distillation, crystallization or chromatography) or bychemical methods (such as formation of salts, crystallization of thelatter and decomposition in alkaline medium). in these operations, thenature of the anion of the salt is immaterial, the only condition beingthat the salt should be well-defined and readily crystallizable.

The compounds of formula I may be converted into acid addition salts andquaternary ammonium derivatives. The acid addition salts may be obtainedby the action of the bases on acids in appropriate solvents. The organicsolvents employed may be, for example, alcohols, ethers, ketones orchlorinated solvents. The salt formed precipitates after optionalconcentration of its solution and is separated by filtration ordecantation. The quaternary ammonium derivatives may be obtained by theaction of the bases on esters, optionally in an organic solvent, atambient temperature or more rapidly with moderate heating.

The compounds of formula I and their acid addition salts and quaternaryammonium derivatives have interesting pharmacodynamic properties. Theyare very active on the central nervous system as antidepressants andanalgesics. They also have good activity as anticonvulsants andtranquillizers. They have given good results in physiological tests onanimals in doses of 5 to 50 mg. per kg. of animal weight. The mostinteresting compounds are those of formula I in which R,, R and R, whichare identical or different, represent hydrogen atom or alkyl of one tofive carbon atoms. especially S-methyl-lO- methylaminol O, ll-dihydrodibenzo[ bflazepine.

For medicinal use, the new compounds may be employed either as bases oras pharmaceutically acceptable acid addition salts or quaternaryammonium derivatives, i.e. salts and derivatives which are nontoxic inthe doses in which they are employed. As examples of pharmaceuticallyacceptable acid addition salts, there may be mentioned salts of mineralacids (such as hydrochlorides, sulphates, nitrates and phosphates) andsalts of organic acids (such as acetates, propionates, succinates,benzoates. fumarates. maleates, tartrates, theophyllineacetates,salicylates, phenolphthalinates and methylenebis-B-hydroxynaphthoates)or substitution derivatives of these acids. As examples ofpharmaceutically acceptable quaternary ammonium derivatives there may bementioned derivatives of mineral or organic esters such as themethochlorides, methobromides, methiodides, ethochlorides, ethobromides.ethiodides, allylchlorides, allylbromides, allyliodides, benzylchlorides," benzyl-bromides, benzyliodides, the methylandethyl-sulphates, the benzene-sulphonates and substitution derivatives ofthese compounds.

The following Examples illustrate the invention.

EXAMPLEI To a solution of l9 g. of S-methyl-l0-hydroximino-l0,l l-

dihydrodibenzo[b,f]eazepine in 200 cm. of hutnnnl at C,

13 g. of sodium are added in portions in 90 minutes. The reactionmixture is then heated under reflux of the butanol for 20 minutes untilthe sodium has completely disappeared. After cooling, 160 cm. ofdistilled water are added and one-half of the solvents is evaporatedunder reduced pressure (20 mm.Hg). cm. of distilled water are added andthe residual butanol is evaporated under normal pressure. The aqueoussuspension obtained is diluted with 700 cm. of distilled water andextracted with 150 cm. of diethyl ether. The separated aqueous solutionis then twice washed with a total of 200 cm. of diethyl ether. Thecombined ethereal solutions are extracted six times with a total of 300cm. of aqueous 2N methane sulfonic acid solution. The combined aqueousacid solutions are made alkaline with 100 cm. of 10 N sodium hydroxidesolution and extracted three times with a total of 350 cm. of diethylether. The combined ethereal solutions are washed 3 times to neutralitywith a total of 300 cm. of distilled water, dried over anhydrous sodiumsulphate and evaporated. The residue (16.5 g.) is dissolved in 20 cm. ofboiling diisopropyl ether. After cooling at 3 C. for 4 hours, thecrystals which have appeared are separated, twice washed with a total of20 cm. ice-cold diisopropyl ether and dried under reduced pressure (20mm.Hg). 1 1.5 g. of 5-methyl-10- amino- 10,1l--dihydrodibenzo[b,f]azepine, m.p. 93 C., are ob tained. The pureproduct (m.p. 96 C.) may be obtained by preparing the hydrochloride inethanol and then converting it into the base and recrystallizing thelatter from acetonitrile.

The starting S-methyl-l-hydroximino-10,1 1- dihydrodibenzo-[b,f]azepinemay be prepared as follows. Methyl-l0-oxo-10,l1-dihydrodibenzo[b,f]azepine (m.p. 104 C.) is prepared by the method ofGerman Pat. No. 1,142,870. The reaction of an excess of hydroxylamine on60 g. of 5- methyl--oxo-10,1 1-dihydrodibenzo[b,f]azepine in aqueousethanolic medium under reflux gives 53.3 g. of 5-methyl-l0-hydroximino-10,1l-dihydrodibenzo[b,f]azepine (m.p. 196 C.).

EXAMPLE II A solution of 6.7 g. of 5-methyl-10-amino-10,11-

dihydrodibenzo[b,flazepine in 360 cm. of ethanol and 40 g.:.

of 30 percent (by weight) aqueous formaldehyde is hydrogenated in thepresence of 18 g. of Raney nickel at normal temperature under a hydrogenpressure of 50 bars for 7 hours. After the catalyst has been filteredoff and washed with ethanol, the clear filtrate is evaporated underreduced pressure (l4mm.Hg). The residue is treated with 150 cm. ofdiethyl ether. The insoluble matter which appears is filtered off andwashed with diethyl ether. The ethereal solution obtained is extractedfour times with a total of 200 cm. of an icecold 2 N aqueousmethanesulphonic acid solution, and the combined acid solutions are madealkaline in the cold with 45 cm. of 10N sodium hydroxide solution. Theoil which separates out is extracted three times with a total of 300 cm.of diethyl ether. The combined ethereal solutions are twice washed witha total of 200 cm. of distilled water, dried over anhydrous potassiumcarbonate, and evaporated. The residue (6.3 g.) is dissolved at boilingpoint in 14 cm. of ethanol and 3 cm. of distilled water. On cooling toabout 50 C. and seeding, crystals appear. The crystallization iscontinued at 3 C. for 2 hours.,The crystals are separated, washed with 11 cm. of icecold 80 percent aqueous ethanol and dried under reducedpressure (14 mm.1-1g). 5 g. of S-methyl-10'dimethylamino- 10,11-dihydrodibenzo[b,f]azepine, m.p. 65 C., are obtained.

EXAMPLE 111 2.2 g. of S-methyl-10-forrnamido-10,1 1-

dihydrodibenz0[b f]azepine are added in small portions in 2 1 minutes toa suspension of 1 1 of lithium aluminum hydride in 180 cm. of anhydrousdiethyl ether, and the mixture is refluxed for 5 hours. The suspension,cooled to 5 C., is hydrolyzed in minutes by adding successively 1.3 cm.of distilled water, 0.95 cm. of 5 N sodium hydroxide solution and 4.3cm. of distilled water. After stirring for 1 hour at ambienttemperature, the precipitate formed is separated and washed three timeswith a total of 120 cm. of boiling methylene chloride The filtrate isevaporated and the residue dissolved in 250 cm. of diethyl ether. Theethereal solution obtained is extracted three times with a total of 150cm. of aqueous 2 N methanesulphonic acid solution. The combined acidsolutions are made alkaline in the cold with 40 cm. of 10N sodiumhydroxide solution. The oil which separates out is extracted three timeswith a total of 300 cm? of diethyl ether.

The combined ethereal solutions are twice washed with a total of 200 cm.of distilled water, dried over anhydrous sodium sulfate and evaporated.To the residue (2 g.) in solution in 10 cm. of isopropanol are added 2cm. of an anhydrous solution of hydrogen chloride in diethyl ether(containing 4 mol of acid per liter of solution). After cooling for 1hour at 3 C., the crystals formed are separated, washed with an ice-coldmixture of 4 cm. of isopropanol and 3 cm. of anhydrous diethyl ether anddried under reduced pressure 1 1 mm.l-lg). 1.9 g. of5-methyl-l0-methy1amino-10,l 1-dihydrodibenzo[b,f]azepine hydrochloride,m.p. 238240 C., are obtained.

The starting S-methyl- 10-formamido-10, 1 ldihydrodibenzo-[b,f]a;epineis prepared as follows. 2 g. of 5- methyl-10-formarnido-l0, 11-dihydrodibenzo[ b,f]azepine (m.p. 142 C.) are obtained by heating 2.25g. of 5-methy1-l0- amino-10,11dihydrodibenzo[b,f]azepine and 14.8 g. ofethyl formate in an autoclave at C. for 2 hours.

EXAMPLE IV 205 g. of sodium amalgam containing 2.5 percent of sodium and6.1 g. of l0-hydroximino-10,1 1-dihydrodibenzo[ b,f]azepine are broughtinto contact at a temperature between 30 and 40 C. in 76 cm. of percentethanol until the sodium of the amalgam is completely consumed. in thecourse of this operation, the pH of the reaction medium is maintained inthe neighborhood of 6 by the addition of a total of 18 cm." of aceticacid. The reaction mixture is diluted with 760 cm. of distilled water.The mercury regenerated in the course of the reaction is eliminated bydecantation. The aqueous phase is made alkaline with 25 cm. of 5N sodiumhydroxide and extracted three times with a total of 750 cm. of diethylether. The combined ethereal solutions are twice extracted with a totalof 200 cm. of aqueous 2 N methanesulphonic acid solution. The combinedaqueous acid solutions are washed with 40 cm. of diethyl ether and thenmade alkaline with 45 cm. of 10 N sodium hydroxide solution. The oilwhich separates out is extracted three times with a total of 750 cm. ofdiethyl ether. The ethereal extracts are washed five times with a totalof 450 cm. of distilled water, dried over potassium carbonate andevaporated. The product obtained (4.7 g., m.p. 122 C.) ischromatographed on 42 g. of alumina eluting with a mixture of benzeneand ethyl acetate. The chromatographed product (2.5 g.) is dissolved in30 cm. of a boiling mixture of cyclohexane and benzene (7:3 by volume).After cooling for 1 hour at 20 C. the crystals which have appeared areseparated, washed twice with a total of 8 cm. of a mixture ofcyclohexane and benzene (7:3 by volume) and dried under reduced pressure(20 mm.Hg). To a boiling solution of 2.4 g. of purified product (m.p.123 C.) in 8 cm. of acetone is addeda boiling solution of 1.1 g. ofanhydrous oxalic acid in 2.5 cm. of acetone. After cooling for half anhour at 3 C., the crystals which have appeared are separated, washedtwice with a total of 10 cm. of acetone, and then with 8 cm of anhydrousdiethyl ether, and dried under reduced pressure (20 mm. Hg.). 2.8 g. of10amino-10,1 1-dihydrodibenzo[b,f]azepine oxalate, m.p. 194 C., areobtained.

The starting 10-hydroximino-10,1 l-dihydrodibenzo[ b,f]azepine may beprepared as follows. IO-Methoxydibenzo[b,f]azepine (m.p. 125 C.) isprepared by the method of Swiss Pat. No. 375,721. The action of dilutehydrochloric acid on 14.0 g. of l0-methoxydibenzo[b,f] azepine, gives8.1 g. of 10-oxo-10,1 1-dihydrodibenzo-[ b,f]azepine (m.p. 141 C.). Theaction of an excess of hydroxylamine on 8 g. of 10-oxo-10,11-dihydrodibenzo[b,f]azepine, in aqueous ethanolic medium under refluxgives 6.1 g. of 10- hydroximino-10,1 1-dihydrodibenzo[b,f]azepine (m.p.1 68 C.).

EXAMPLE V dihydroflibenzow,f]azepine are brought into contact at 70 C.

in 320 cm. of 95 percent ethanol until the sodium of the amalgam hasbeen completely consumed. 1n the course of this operation, the pH of thereaction medium is maintained in the neighborhood of 6 by the additionof a total of 30 cm. of acetic acid. When the reaction has ended, theregenerated mercury is eliminated by decantation. The aqueous ethanolphase is concentrated under reduced pressure (20 mm.l-lg) to a volume ofabout 50 cm. and then diluted with 500 cm. of distilled water and madealkaline with aqueous sodium carbonate solution. The oil in suspensionis extracted three times with a total of 300 cm. of diethyl ether andthe combined ethereal solutions are extracted five times with 500 cm. ofaqueous 2 N methanesulphonic acid solution. The aqueous acid solutionsare made alkaline with 100 cm. of 10 N sodium hydroxide solution, andthe oil which separates out is extracted three times with a total of 450cm. of diethyl ether. The ethereal extracts are twice washed with atotal of 200 cm. of distilled water, dried over anhydrous sodiumsulfate, and evaporated. The residue obtained (7.5 g.) is dissolved in20 cm. of boiling heptane. After cooling for 24 hours at 3 C., thecrystals which have appeared are separated, washed with 10 cm. ofheptane and dried under reduced pressure (20 mm.Hg). The productobtained (6.7 g., m.p. 89 C.) is purified by conversion into thefumarate which is recrystallized from ethanol (8.2 g., m.p. 200 C.) andreconverted into the base, which is then crystallized from heptane. 4.6g. of -ethyl-l0- amino-10,11-dihydrodibenzo[b,f]-azepine, m.p. 90 C.,are obtained.

The starting 5-ethy1- 1 O-hydroximinol 0,1 1-dihydrodibenzo-[b,f]azepine may be prepared as follows.Methoxydibenzo[b,f]azepine is prepared as indicated in example IV. Thereaction of sodamide and the n of ethyl iodide H inhexamethylphosphotriamide on g. of 20-methoxydibenzo[b,f]azepine give15.4 g. of 5-ethyl-lO-methoxydibenzo[b,f]azepine (m.p. 180 C.). Theaction of dilute hydrochloric acid on 12.7 g. of5-ethyl-l0-methoxydibenzo[ b,f]azepine gives 10.7 g. of5-ethyl-l0-oxo-l0,l1- dihydrodibenzolbflazepine (m.p. 120 C.). Theatlion of an excess of hydroxylamine on 10.5 g. of 5-ethyl-10-oxo-10,lldihydrodibenzo[b,f]azepine gives 10.8 g. of 5 ethyll0- hydroximino- 10:1 l d i hydrodiben2o[b,f]azepine (m.p. 207 C.

EXAMPLE V1 327 g. of sodium amalgam containing 2.5 percent of sodium and1 1.6 g. of S-benzyl-lO-hydroximino-10,1 ldihydrodibenz0[b,f]azepine arebrought intp ontacttug/31g in 320 cm. of 95perze iitqlianol until thesodium of the amalgam has been completely consumed. In the course ofthis operation, the pH of the reaction medium is maintained in theneighborhood of 6 by the addition of a total of 25 cm. of acetic acid.The mercury regenerated in the course of the reaction is eliminated bydecantation. The aqueous ethanol phase is concentrated under reducedpressure (20 mm.Hg) to a volume of about 100 cm. and then diluted with600 cm. of distilled water and made alkaline with aqueous sodiumcarbonate solution. The oil in suspension is extracted three times witha total of 600 cm. of diethyl ether. The combined ethereal solutions areextracted four times with a total of 400 cm. of an aqueous 2 Nmethanesulphonic acid solution. The aqueous acid solutions are madealkaline with 85 cm. of 10 N sodium hydroxide solution, and the oilwhich separates out is extracted three times with a total of 450 cm. ofdiethyl ether. The ethereal extracts are twice washed with a total of200 cm. of distilled water, dried over anhydrous sodium sulphate, andevaporated. The residue obtained 10.1 g.) is dissolved in 28 cm. ofanhydrous ethanol and the solution is filtered and treated at 3 C. with16.8 cm. ofa 1.95 N methanesulphonic acid solution in ethanol. Aftercooling for 1 hour at 3 C., the crystals which have appeared areseparated, washed with 10 cm. of ice-cold anhydrous ethanol and thenwith 10 cm. of anhydrous diethyl ether and dried under reduced pressure(20 benzyl-10-oxo-10,11-dihydrodibenzo-[b,f]azepine gives 12.0 1

g. of S-benzyl-10hydroximino-10,1 l-dihydrodibenzo[ b,f] azepine (m.p.202 C.).

EXAMPLE V" 14.9 g. of S-methyl-10-acetylamino-10,1 l-dihydrodibenzo-[b,f]azepine are added in small portions in 2 minutes to a suspension of6.35 g. of lithium aluminum hydride in 700 cm. of anhydrous diethylether. The mixture is heated under reflux for 5 hours and the suspensionis then cooled to 5 C. and hydrolyzed by the addition of 7.3 cm. ofdistilled water, followed by 5.45 cm. of 5 N sodium hydroxide, andfinally 25 cm. of distilled water. After stirring for 1 hour at 20 C..the precipitate formed is separated and twice washed with a total of 100cm. of boiling methylene chloride. The filtrate is thrice extracted witha total of cm. of aqueous 2 N methanesulphonic acid solution. Theaqueous acid solutions are washed with 40 cm. of diethyl ether and thenmade alkaline with 18 cm. of 10 N sodium hydroxide solution. The oilwhich separates out is twice extracted with a total of cm.- of diethylether and the ethereal extracts are washed three times with a total ofcm. of distilled water, dried over potassium carbonate and evaporated.The residue obtained 12.4 g.) is purified by conversion into thefumarate which is crystallized from ethanol (14 g., m.p. -138 C.) andreconversion into the base. The purified product (7.9 g.) is dissolvedin 30 cm of anhydrous diethyl ether and the solution is treated at 3 C.with 16.1 cm. of a 1.94 N methanesulphonic acid solution in ethanol.After cooling for 2 hours at 3 C., the crystals which have appeared areseparated, twice washed with a total of 20 cm. of anhydrous diethylether, and dried under reduced pressure (20 mm.Hg). 10.2 g. of S-methyllO-ethylamino- 1 0,1 l-dihydrodibenzo- [b,f]azepine methanesulphonic,m.p. 196 C., are obtained.

The starting S-methyl- 1 O-acetylamino- 1 0,1 1-dihydrodibenzo-[b,f]azepine may be prepared as follows. 5-Methy1-10-amin0-10,l 1dihydrodibenzo[b,f]azepine (m.p. 96 C.) isprepared as described in Example 1.

The action of acetic anhydride in pyridine on 36 g. of 5- methyl- 1O-aminol 0,1 1-dihydrodibenzo[b,f]azepine gives 41.4 ofS-methyl-l0-acetylamino-10,l 1- dihydrodibenzo[b,f]eazepine (m.p. 187C.).

EXAMPLE Vlll A solution of 8.9 g. of 5methyl-10-( N-acetyl-N-ethylamino)-l0,1l-dihydrodibenzo[b,f]azepine in 40 cm. of anhydrousdiethyl ether is added in 7 minutes to a suspension of 3.4 g. of lithiumaluminum hydride in cm. of anhydrous diethyl ether at 20 C. Afterheating under reflux for 5 hours, the suspension is cooled to 5 C. andhydrolyzed by the addition of 3.9 cm? of distilled water, followed by2.9 cm. of 5 N sodium hydroxide, and finally 13.2 cm. of distilledwater. After stirring for 1 hour at ambient temperature, the precipitateformed is separated and twice washed with a total of 70 cm. of boilingmethylene chloride. The filtrate is evaporated under reduced pressure(20 mm.Hg). The residue (8.5 g.) is dissolved in 30 cm. of diethyl etherand the ethereal solution obtained is twice extracted with a total of 70cm. of ice-cold aqueous 2 N methanesulphonic acid solution. The combinedaqueous acid solutions are made alkaline at 3 C. with 18 cm of 10 Nsodium hydroxide solution and the oil which separates out is extractedthree times with a total of 1 30 cm. of diethyl ether. The extracts aretwice washed with a total of 200 cm. of distilled water, dried overanhydrous magdihydrodibenzo[b,f]azepine may be prepared as follows. 5-

Methyl-1o-ethylamino-l lfil-dihydrodibenakfi bfiaiepirie is prepared asdescribed in example VII. The action of acetic anhydride in pyridine on8.4 g. of 5-methyl-l0-ethylamino-l0,l l -dihydrodibenzo[b,f]azepinegives 8.9 g. of 5-methyl-l0(N- acetyl-N-ethylamino l 0,1l-dihydrodibenzo[ b,f] azepine (as a crude oily product).

EXAMPLE 1X A solution of 10 g. of 5-methyl-l0-( N-formyl-N-ethylamino)-l0,l l-dihydrodibenzo[b,f]azepine in 200 cm. of anhydrousdiethyl ether is added in 10 minutes to a suspension of 4.1 g. oflithium aluminum hydride in 200 cm. of anhydrous diethyl ether at 20 C.After heating under reflux for 4 hours, the suspension is cooled to 5 C.and hydrolyzed by the addition of 4.8 cm. of distilled water, followedby 3.5 cm. 3 of 5 N sodium hydroxide, and finally 15.8 cm. of distilledwater. After stirring for 15 minutes at 5 C., the precipitate formed isseparated and twice washed with a total of 200 cm. of boiling methylenechloride. The filtrate is twice extracted with a total of 200 cm. ofaqueous 2 N methanesulphonic acid solution and three times with a totalof 150 cm. of distilled water. The combined aqueous acid solutions aremade alkaline with 70 cm. of 5 N sodium hydroxide and the oil whichseparates out is extracted with 100 cm. of diethyl ether. The aqueousalkaline phase is saturated with sodium chloride and then again twiceextracted with a total of 200 cm. of diethyl ether. The combinedethereal solutions are dried over potassium carbonate and evaporated.The residue obtained (8.0 g.) is dissolved in 4 cm. of boiling ethylacetate and the solution obtained is treated with a boiling solution of3.5 g. of maleic acid in 25 cm. of ethyl acetate. After cooling at 3 C.for 2 hours, the crystals which have appeared are separated, twicewashed with a total of 10 cm. of ethyl acetate and then twice with atotal of 20 cm. of anhydrous diethyl ether and dried under reducedpressure (20 mm.l-lg). 10.5 g. of S-methyl-lO- methylethylamino-10,lldihydrodibenzo-[b,f]azepine maleate, m.p. 135C., are obtained.

The starting S-methyll N-formyl-N-ethylamino )-N10,11-dihydrodibenzo[b,f]azepine may be prepared as follows. 5-Methyl-l0-ethylamino-10,1 l-dihydrodibenzo [b,f]azepine is prepared asdescribed in example VII. The action of an excess of formylaceticanhydride at ambient temperature on 9.1 g. ofS-methyl-l0-ethylamino-l0,l ldihydrodibenzo[b,f]azepine gives g. ofS-methyl-lO-(N- formyl-N-ethylamino)-10,1 1 dihydrodibenzo[b,f] azepine(as a crude oily product).

EXAMPLE X To a solution of 3.5 g. of S-methyl-lO-methylamino-10,1ldihydrodibenzo[b,f]azepine in 10 cm. of anhydrous dimethylformamidecontainin g lfl g. of sodium bicarbonate a solution of 1.39 g. ofdimethylsulphate in 5 amid? anhydrous dimethylformamide is added in thecourse of 4 minutes. The suspension obtained is agitated at ambienttemperature for 3 hours. 150 cm. of ice-cold distilled water and 10 cm.of 10 N sodium hydroxide solution are added, and the mixture isextracted three times with a total of 180 cm. of diethyl ether. Theunited ethereal solutions are extracted twice with a total of 60 cm. ofaqueous N methanesulphonic acid. The aqueous acid solutions are unitedand made alkaline with 10 cm. of 10 N sodium hydroxide solution, and thealkaline mixture is extracted three 3 times with a total of 120 cm. ofdiethyl ether. The etherealsolutions are united, dried over potassiumcarbonate, and evaporated. The residue 1.6 g.) is converted into thehydrochloride in ethanol, and then reconverted into the base which isrecrystallized from aqueous ethanol to give 0.9 g. ofS-methyl-l0-dimethylamino-10,l l-dihydrodibenzo[ b,f] azepine, m.p.65-66 C.

EXAMPLE X1 A solution of 0.53 g. of S-methyl-lO-(N-cyano-N-methylamino)- l 0,1 l-dihydrodibenzo[ b,f]azepine (m.p. -87 C.) in 10cm. of n-butanol is heated under reflux for 8 hours in the presence of0.66 g. of potassium hydroxide. After cooling, cm. of distilled waterare added, and the mixture is extracted twice with a total of 100 cm. ofdiethyl ether. The united ethereal extracts are washed with 25 cm ofdistilled water, and then extracted twice with a total of 100 cm. ofice-cold aqueous N methanesulphonic acid. The united aqueous acidsolutions are made alkaline with 25 cm. of 10 N sodium hydroxidesolution and extracted three times with a total of cm. of diethyl ether.The united ethereal extracts are washed with 20 cm." of distilled water,dried over anhydrous magnesium sulphate and evaporated. The residueobtained (0.40 g.) is converted in isopropanol into the hydrochloride ofS-methyll O-methylaminol 0,1 ldihydrodibenzo[b,f]eazepine (0.42 g.) m.p.237-240 C.

EXAMPLE Xll A solution of 1.0 g. of 5-methyl-10(N-ethoxycarbonyl-N-methylamino)-10,l l-dihydrodibenzo[b,f]azepine (b.p. l72l75 C./0.lmm.Hg) in 5 cm. of n-butanol is heated under reflux for 4 hours in thepresence of 1.0 g. of potassium hydroxide. After cooling, 100 cm. ofdistilled water are added, and the mixture is extracted twice with atotal of 120 cm. of diethyl ether. The united ethereal extracts arewashed with 25 cm. of distilled water and then extracted twice with atotal of 100 cm. of ice-cold aqueous N methanesulphonic acid solution.The aqueous acid solutions are combined and made alkaline with 25 cm. of10 N sodium hydroxide solution, and extracted twice with a total of 120cm. of diethyl ether. The united ethereal extracts are washed with 20cm. of distilled water, dried over anhydrous sodium sulfate, andevaporated. The residue (0.31 g.) is converted in isopropanol into thehydrochloride of S-methyl-l0-methylamino-l0,ldihydrodibenzo[b,f]e-azepine (0.27 g.), m.p. 238-240C.

EXAMPLE Xlll A solution of 0.53 g. of 5-methyl-l0-(N-formyl-N-methylamino)-l0,ll-dihydrodibenzo(b,f]azepine in 10 cm. of n-butanol isheated under reflux for 8 hours in the presence of 0.66 g. of potassiumhydroxide. After cooling, 100 cm. of distilled water are added, and themixture is extracted twice with a total of 100 cm. of diethyl ether. Theunited ethereal extracts are washed with 25 cm. of distilled water, andthen extracted twice with a total of 100 cm. of ice-cold aqueous Nmethanesulphonic acid solution. The united aqueous acid solutions aremade alkaline with 25 cm. of 10 N sodium hydroxide solution, andextracted three times with a total of 120 cm. of diethyl ether. Theunited ethereal extracts are washed with 30 cm. of distilled water,dried over anhydrous magnesium sulphate, and evaporated. The residueobtained (0.39 g.) is converted in isopropanol into the hydrochloride of5-methyll O-methylamino- 1 0,1 l-dihydrodibenzo[b,f]azepine (0.39 g.),m.p. 237-240C.

The S-methyl- 1 0-(N-formyl-N-methylamino)- l 0,1ldihydrodibenzo-[b.flazepine used as starting material can be preparedas follows. S-Methyll O-formamidol 0,1 1- dihydrodibenz0[b,f]azepine isprepared the manner des'cibedin'examplelll. By the action of sodiumhydride, followed by dimethyl sulphate, at ambient temperature inanhydrous tetrahydrofuran, on 2.5 g. of 5-methyl-l0-formamido-l0,1l-dihydrodibenzo-[b,f]azepine, 1.8 g. of 5-methyl-10-(N-formyl-N-methylamino)-10, l ldihydrodibenzo[b,f]azepine,m.p. 95 C., are obtained.

EXAMPLE XIV 0.58 g. of sodium is added in portions over 8 minutes to asuspension of 0.98 of 5-methyl-l0-(N-methyl-N- tosylamino)-l0,ll-dihydrodibenzo[b,f]azepine in 15 cm. of n-butanol at 100 C. Thereaction mixture is then heated under reflux for 30 minutes until thesodium has completely disappeared. After cooling, 100 cm. of distilledwater are added, and the mixture is extracted twice with a total of 100cm. of diethyl ether. The united ethereal extracts are extracted twicewith a total of 80 cm. of ice-cold aqueous N methanesulphonic acidsolution. The united aqueous acid solutions are made alkaline with 20cm. of 10 N sodium hydroxide solution, and extracted twice with a totalof 120 cm. of diethyl ether. The united ethereal extracts are dried overpotassium carbonate and evaporated. The reside (0.56 g.) is dissolved ina mixture of 3 cm. of isopropanol and 3 cm. of diethyl ether. 0.6 cm. ofa 4 N anhydrous solution of hydrogen chloride in diethyl ether is added,and after cooling for 1 hour at 3 C., the crystals formed are separated,washed with 2 cm. of a mixture of isopropanol and diethyl ether (1:1),then twice with a total of 4 cm. of diethyl ether, and finally driedunder reduced pressure (20 mm.l-lg). 0.6 g. ofthe hydrochloride of5-methyll methylamino-l0,l ly zol tflazsain l,m-i 37?2 0i9 ar sm The-methyl- (N -methyl-N -tosylamino) -F), 1 l dihydrodibenzo[b,flazepineused as starting material can be prepared as enews? 5 lVlethyl lUamiholfill dihydrodibenzo[b,flazepine (m.p. 96 C.) is prepared by the methodof example ll Thereact ioh o f 1.0 ETBTp tolEEnest JTfo nyl chloride on2.24 g. of 5-methyl-l0-amino-l0,l ldihydrodibenzo[b,flazepine inpyridine at ambient temperature gives 2 v g. of 5351514 (YuEylammjldihydrodibenzo[b,f1azepine m.p. 158 C. The reaction of 0.75 g. ofdimethylsulphate on 0.95 g. of S -meth yFl (Ytosylamino-10,1l-dihydrodibenzo[b,f]azepine in ethanol in the presenceof an acid-binding agent gives 0.74 g. of 5- EXAMPLE XV A solution of4.9 g. of S-methyl-lO-(N-ethoxycarbonyl-N- methylamino)-l0,ll-dihydrodibenzo[b,f]azepine in 75 cm. of anhydrous diethyl ether isadded in 25 minutes to a suspension of 1.25 g. of lithium aluminumhydride in 75 cm. of anhydrous diethyl ether. The mixture is refluxedfor 3 hours. The suspension is then cooled to 5 C. and hydrolyzed in 1hour by the successive addition of 1.45 cm. of distilled water, 1.1 cm.of 5 N sodium hydroxide solution, and 4.9 cm. of distilled water. Theprecipitate formed is filtered off and washed four times with a total of200 cm. of diethyl ether. The filtrate is extracted twice with a totalof 100 cm. of ice-cold aqueous 2 N methanesulphonic acid, and then with50 cm? of distilled water. The united aqueous acid solutions are madealkaline with cm. of 10 N sodium hydroxide solution and then extractedthree times with a total of 240 cm. of diethyl ether. The etherealsolutions are united and washed with cm. of distilled water, dried overanhydrous magnesium sulphate, and evaporated. The residue obtained (3.8g.) is dissolved in 7 cm. of lukewarm ethanol, 1.7 cm. of distilledwater are added, and crystallization begins. After 16 hours cooling at 3C., the crystals which have appeared are separated, washed with 1.5 cm.ofa mixture of ethanol and distilled water (4:1 and dried under reducedpressure (20 mm.l-lg). 3.6 g. of 5- methyl- 1 O-dimethylaminol 0,1l-dihydrodibenzo[b,f]azepine, m.p. 6566 C. are obtained.

The S-methyl-10-(N-ethoxycarbonyl-N-methylamino)- l0,ll-dihydrodibenzo[b,f]azepine used as starting material can be preparedas follows: S-Methyl-10-methy1amino-l0,l ldihydrodibenzo[b,f]azepine isprepared by the method of ex-z ample Ill. The action of ethylchlorofiarmatein benzene in the presence of triethylamine on 13.9 g. ofS-methyl-lO- methyIamino-l0,l l-dihydrodibenzo[b,f]azepine, gives 10.1g. of 5 -methyl-l0-(N-ethoxycarbonyl-N-ethylamino)-10,1ldihydrodibenzo[b,f]azepine, b.p. l72-l75 C./0.l mmllg.

The invention includes within its scope pharmaceutical compositionscomprising, in association with a pharmaceutically acceptable carrier orcoating, at least one 10,1 1- dihydrodibenzo[b,f]eazepine derivative offormula 1 or a nontoxic acid addition salt or quaternary ammoniumderivative thereof. These compositions may be in a form suitable fororal, parenteral, or rectal administration.

Solid compositions for oral administration include tablets, pills,powders, or granules. In such solid compositions, the active compound ismixed with one or more inert diluents such as sucrose, lactose orstarch. These compositions may also comprise, as is normal practice,substances other than diluents, e.g. lubricants such as magnesiumstearate.

Liquid compositions for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixerscontaining inert diluents such as water or paraffin oil. Thesecompositions may also comprise substances other than diluents, forexample wetting agents, sweetening agents, perfumes and preservatives.

The compositions according to the invention for parenteraladministration may be aqueous or nonaqueous sterile solutions,suspensions or emulsions. As solvent or vehicle, there may be employedpropylene glycol, polyethylene glycol, vegetable oils, more particularlyolive oil, and injectable organic esters, for example ethyl oleate.These compositions may also contain adjuvants, more particularly wettingagents, emulsifiers and dispersing agents. The sterilization may beeffected in various ways, for example with the aid of a bacteriologicalfilter, by incorporating sterilizing agents in the composition, byirradiation or by heating. The compositions may also be prepared in thefonn of sterile solid compositions which may be dissolved at the time ofuse in sterile water or any other sterile injectable medium.

The compositions for rectal administration are suppositories whichcontain, in addition to the active compound, excipients such as cacaobutter or suppository wax.

The dose employed depends upon the desired therapeutic effect, the routeof administration and the duration of treatment. When orallyadministered, generally between 10 and 250 mg. per day of active productis administered to an adult.

The following examples illustrate pharmaceutical compositions accordingto the invention:

EXAMPLE A Tablets having the following composition are prepared by theusual technique:

S-methyl-lO-amino-IOJ l-dihydrodihenzo[b.1'lazepine 10mg. starch mg.

colloidal silica 32 mg. magnesium stcurute 3 mg.

EXAMPLE B Tablets having the following composition are prepared by theusual technique:

S-methyl-lO-rnethylamino-10,1 l-dihydrodibenzo[b,f]-

azepine hydrochloride 28.9 mg. starch 86.1 mg. colloidal silica 32 mg.magnesium stearate 3 mg.

We claim: 1. A 10,11-dihydrodibenzo[b,f]azepine derivative of theformula:

and its pharmaceutically acceptable acid addition salts, in which R andR are the same or different and each represent hydrogen or alkyl of oneto five carbon atoms, and R, is hydrogen, alkyl of one to five carbonatoms, or benzyl.

2. A 10,! l-dihydrodibenzo[b,f]azepine derivative as claimed in claim 1and its acid addition salts and quaternary ammonium derivatives to whichR and R are each hydrogen or alkyl of one to five carbon atoms and R, ishydrogen or alkyl of one to five carbon atoms.

6. A derivative as claimed in claim I, which is lO-aminol0,ll-dihydrodibenzo[b,f]azepine or a pharrnaceutically acceptable acidaddition salt.

7. A derivative as claimed in claim I, which is S-ethyl-lO-amino-10,1l-dihydrodibenzo[b,f]azepine or 'a pharmaceutically acceptableacid addition salt.

8. A derivative as claimed in claim 1, which is S-benzyl-lO-amino-10,1l-dihydrodibenzo[b,f]azepine or a pharmaceutically acceptableacid addition salt.

9. A derivative as claimed in claim 1, which is 5-methyl-l0-ethylamino-lO,l l-dihydrodibenzo[b,f]azepine or a pharrnaceuticallyacceptable acid addition salt.

10. A derivative as claimed in claim 1, which is S-methyl-IO-diethylamino- 10,1 l-dihydrodibenzo[b,f]azepine or apharrnaceutically acceptable acid addition salt.

11. A derivative as claimed in claim I, which isS-methyll0-methylethylamino-l0,l l-dihydrodibenzo[b,f]azepine or apharrnaceutically acceptable acid addition salt.

2. A 10,11-dihydrodibenzo(b,f)azepine derivative as claimed in claim 1and its acid addition salts and quaternary ammonium derivatives in whichR and R'' are each hydrogen or alkyl of one to five carbon atoms and R1is hydrogen or alkyl of one to five carbon atoms.
 3. A derivative asclaimed in claim 1, which is5-methyl-10-methylamino-10,11-dihydrodibenzo(b,f)azepine or apharmaceutically acceptable acid addition salt.
 4. A derivative asclaimed in claim 1, which is5-methyl-10-amino-10,11-dihydrodibenzo(b,f)azepine or a pharmaceuticallyacceptable acid addition salt.
 5. A derivative as claimed in claim 1,which is 5-methyl-10-dimethylamino-10,11-dihydrodibenzo(b,f)azepine or apharmaceutically acceptable acid addition salt.
 6. A derivative asclaimed in claim 1, which is 10-amino-10,11-dihydrodibenzo(b,f)azepineor a pharmaceutically acceptable acid addition salt.
 7. A derivative asclaimed in claim 1, which is5-ethyl-10-amino-10,11-dihydrodibenzo(b,f)azepine or a pharmaceuticallyacceptable acid addition salt.
 8. A derivative as claimed in claim 1,which is 5-benzyl-10-amino-10,11-dihydrodibenzo(b,f)azepine or apharmaceutically acceptable acid addition salt.
 9. A derivative asclaimed in claim 1, which is5-methyl-10-ethylamino-10,11-dihydrodibenzo(b,f)azepine or apharmaceutically acceptable acid addition salt.
 10. A derivative asclaimed in claim 1, which is5-methyl-10-diethylamino-10,11-dihydrodibenzo(b,f)azepine or apharmaceutically acceptable acid addition salt.
 11. A derivative asclaimed in claim 1, which is5-methyl-10-methylethylamino-10,11-dihydrodibenzo(b,f)azepine or apharmaceutically acceptable acid addition salt.